Metal-containing ionic liquids as efficient catalysts for hydroxymethylation in water

Article abstract of DOI:10.1002/ejoc.200800323

The iron-containing ionic liquid butylmethylimidazolium tetrachloroferrate (bmim-FeCl₄) proved to be an efficient and recyclable catalyst for the hydroxymethylation of β-keto esters using aqueous formaldehyde and a low catalyst loading of up to

Full text of DOI:10.1002/ejoc.200800323

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800323
Metal-Containing Ionic Liquids as Efficient Catalysts for Hydroxymethylation
in Water
Katharina Bica[a] and Peter Gaertner*[a]
Keywords: Ionic liquids / Iron / Water chemistry / Hydroxymethylation / Lactones
The iron-containing ionic liquid butylmethylimidazolium tet-
rachloroferrate (bmim-FeCl4) proved to be an efficient and
recyclable catalyst for the hydroxymethylation of β-keto es-
ters using aqueous formaldehyde and a low catalyst loading
of up to 0.1 mol-% without co-solvents or additional surfac-
tants. An useful and high-yielding approach to hydroxymeth-
ylated keto esters as well as to 3-disubstitued butyrolactones
via tandem hydroxymethylation–lactonization could thus be
established.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
ficial and enable neutral and mild conditions. Recent ad-
vances in the iron-catalyzed hydroxyformylation include the
work of Lecomte and Bolm who described iron(III)-cata-
lyzed tandem sequentional methanol oxidations and aldol
coupling and of Ogawa and Kobayashi who described sur-
factant-promoted hydroxymethylation of various 1,3-dicar-
bonyl compounds in water.[8,9] Large catalyst amounts (10
and 5%, respectively) where used, and in case of tandem
oxidation/hydroxylation a substoichiometric amount of al-
dehyde was added.
Introduction
Recently, great effort has been laid in the development of
alternative reaction media, and the number of publications
dealing with reactions in aqueous systems, ionic liquids or
supercritical solvents is constantly growing.[1] Ionic liquids
have been successfully used as immobilizing reagents for
transition metal catalysts, combining the advantages of
both homogeneous and heterogeneous catalysis and often
leading to improved process performance.[2] Beyond their
application as mere reaction media, ILs with metal-contain-
ing anions have been successfully used as catalysts them-
selves, e.g. in Friedel–Crafts alkylation.[3] Since iron is one
of the most inexpensive and non-pollutant metals the scope
for iron-catalyzed organic reactions is of great interest and
constantly growing.[4] As a part of our program to explore
the full potential of the use of transition metal-containing
ionic liquids as catalysts in chemical transformations,[5] we
wanted to demonstrate the very efficient role of the easily
prepared iron-containing ionic liquid butylmethylimida-
zolium tetrachloroferrate (bmim-FeCl4, 1) in the hydroxy-
methylation of β-keto esters.
Results and Discussion
For initial screening we investigated the reaction of β-
keto ester 6 and aqueous formaldehyde solution with
10 mol-% of metal-containing ionic liquids 1–5 as catalyst
to yield hydroxymethylated product 7 that is of interest as
intermediate to antiviral drugs (Scheme 1).[10] The metal-
containing IL should not only act as catalyst for hydroxy-
methylation of β-oxo esters under mild conditions, but re-
cyclation should also be possible. Furthermore, the IL
should promote the reaction between the aqueous formal-
dehyde solution and β-oxo esters that are not soluble in
water.
Aldol condensation with formaldehyde is a classical C–
C bond-forming reaction and one of the most useful pro-
cedures for the introduction of a C1 moiety.[6,7] However,
many C1 homologation reactions are limited by the use of
gaseous formaldehyde, solid paraformaldehyde or trioxane
which has to be depolymerised prior to its use. Therefore,
the application of an aqueous formaldehyde solution com-
bined with transition metal catalysis would be highly bene-
Scheme 1. IL-catalyzed hydroxymethylation using aqueous formal-
dehyde.
[a] Institute of Applied Synthetic Chemistry, Vienna University of
Technology,
Getreidemarkt 9/163-OC, 1060 Vienna, Austria
Fax: +43-1-58801-15499
Indeed, no co-solvent was necessary since homogeneous
conditions were observed even after addition of aqueous
formaldehyde solution. Moreover, less formaldehyde solu-
E-mail: peter.gaertner@tuwien.ac.at
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 3453–3456
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3453

K. Bica, P. Gaertner
SHORT COMMUNICATION
tion (1.2 equiv.) was necessary compared to the surfactant-
Since ionic liquids have proved to be excellent solvents
promoted hydroxymethylation which was run with 1.5 up for the immobilization of transition metal catalysts, we were
to 10 equiv.[8] In each case, the desired reaction was ob- particularly interested if the iron-containing ionic liquid 1
served, but among those, FeIII, NiII and CoII ionic liquids could be recycled if used as catalyst itself without further
proved superior and gave product 7 in good yield, whereas immobilization. After the product was isolated via kugel-
considerably lower yield was obtained with CuII and TiIV rohr distillation, the remaining material was directly sub-
salts (Table 1, entries 1–5). Best results could be achieved jected to the next run without further work-up or purifica-
with the iron-containing ionic liquid bmim-FeCl4 (1), which tion. Fresh starting materials were added and the reaction
showed complete conversion within 5 min only. Due to the was successfully run again showing only a minor decrease
fast reaction but also to the very low excess of formalde- in yield, although longer reaction times were required
hyde used, we never observed polymerization of formalde- (Table 3, entries 2–5).
hyde in the iron-catalyzed hydroxymethylation.
Table 3. Recyclation of bmim-FeCl4 1.
Run[a]
Conditions
Yield[b]
Table 1. Screening of metal-containing ILs as catalysts for hydroxy-
methylation.
1
2
3
4
5
room temp., 15 min
room temp., 30 min
room temp., 30 min
room temp., 60 min
room temp., 120 min
87
81
88
75
78
Entry[a]
Catalyst
Yield[b]
1
2
3
4
5
bmim-FeCl4
bmim2-NiCl4
bmim2-CoCl4
bmim2-CuCl4
bmim-TiCl5
1
2
3
4
5
90
77
76
44
32
[a] Reactions were carried out with 5 mmol β-keto ester 6, 6 mmol
aq. HCHO and 0.05 mmol bmim-FeCl4 (1). [b] Isolated yield after
kugelrohr distillation.
[a] Reactions were carried out with 5 mmol keto ester 6, 6 mmol
aq. HCHO and 0.05 mmol ionic liquid at room temp. for 60 min.
[b] Isolated yield after flash column chromatography.
When keto ester 8 was applied, longer reaction times
were necessary, nevertheless 73% of 9 could be isolated af-
ter stirring overnight (Table 4, entry 1). β-Keto esters 10
and 14 reacted also well whereas keto ester 12 showed only
Encouraged we investigated the iron-catalyzed reaction
in detail and lowered the catalyst concentration: if 1 mol-%
of the iron salt 1 was used, the reaction proceeded smoothly
in 15 min at room temp. with an isolated yield of 87%
(Table 2, entry 2). For comparison, when the reaction is
performed under the same conditions applying FeCl3 as cat-
alyst, a lower yield of 73% only is obtained (entry 5).
Table 4. Results of various 1,3-dicarbonyl compounds.
Table 2. Optimization of catalyst concentration.
Entry[a]
Catalyst
Conditions
Yield[b]
1
2
3
4
5
10 mol-% 1
1 mol-% 1
0.1 mol-% 1
0.1 mol-% 1
1 mol-% FeCl3
room temp., 5 min
room temp., 15 min
room temp., 16 h
80 °C, 15 min
90
87
88
92
73
room temp., 15 min
[a] Reactions were carried out with 5 mmol of β-keto ester 6 and
6 mmol aq. HCHO. [b] Isolated yield after flash column
chromatography.
Further reduction of the catalyst loading up to 0.1 mol-
% resulted in longer reaction times and stirring overnight
was required to allow complete conversion and maintain
the yield of 88%. Nevertheless, this problem could be easily
dealt with by elevating the reaction temperature: The reac-
tion proceeded in 15 min only if run at 80 °C and gave an
excellent isolated yield of 92% (Table 2, entries 3 and 4).
Further studies showed that the use of aqueous formalde-
hyde solution is indeed necessary to ensure conversion:
when treated with paraformaldehyde or trioxane in the
presence of 1 mol-% of bmim-FeCl4 (1), no conversion of
keto ester 6 but also no polymerization of formaldehyde
was observed neither at room temp. nor after heating to
80 °C overnight.
[a] Reactions were carried out with 5 mmol keto ester 6, 6 mmol
aq. HCHO and 0.05 mmol bmim-FeCl4 (1) at room temp. until
TLC indicated complete conversion. [b] Isolated yield after flash
column chromatography.
3454
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3453–3456

Metal-Containing Ionic Liquids as Efficient Catalysts
slow conversion and a considerable lower yield of 33% knew route to 3-disubstituted butyrolactones was estab-
(Table 4, entries 2, 3 and 4). Unfortunately, almost no con- lished. Further aspects towards stereoselective hydroxy-
version was observed when diethyl malonate 16 was applied methylation using an iron-containing chiral ionic liquid as
(Table 4, entry 5). 2-Acetylbutyrolactone 16 exhibited also well as the influence of the cation are currently investigated.
a good yield of 68% (Table 4, entry 6).
In case of diethyl acetylsuccinate 20, only very slow con-
Experimental Section
version was observed at room temp. using 1 mol-% of cata-
lyst. On the other hand, when heated to 80 °C in the pres-
ence of 10 mol-% of 1 complete conversion was achieved in
2 h. Hydroxymethylation followed by in-situ lactonization
gave lactone 21 as single product in 85% isolated yield
General: Butylmethylimidazolium chloride (bmim-Cl) was synthe-
sized and recrystallized as reported in the literature.[11] Bmim-FeCl4
(1) was synthesized from bmim-Cl and FeCl3·6H2O according to
the literature.[5,12] All other ionic liquids 2–5 are also known in the
(Table 5, entry 1). This reaction worked equally well with literature and were prepared from bmim-Cl and the corresponding
anhydrous metal chloride by mixing equimolar amounts under an
atmosphere of dry nitrogen. Starting materials 22, 24, 26 and 28
were prepared according to literature procedures.[13] For TLC-
analysis precoated aluminum-backed plates (silica gel 60 F254,
various acylated succinic esters, and thus, a general ap-
proach to 3-disubstituted butyrolactones could be devel-
oped (entries 1–5).
1
Merck) were used. H and 13C NMR spectra were recorded on a
Table 5. 3-Disubstituted butyrolactones via in situ hydroxymethyl-
Bruker AC 200 in CDCl3 at 200 and 50 MHz, respectively, using
the solvent peak as reference. Elemental analyses were carried out
at Vienna University, Department of Physical Chemistry, Labora-
tory for Microanalysis, Währinger Str. 42, 1090 Vienna, Austria.
GC/MS analyses were conducted on a VOYAGER Quadrupol
(Thermo Finnigan) directly interfaced to a GC 8000 TOP gas chro-
matograph using a BGB-5 (30 mϫ0.32 mm i.d., 1.0 µm film thick-
ness) cross-bonded dimethyl polysiloxane capillary column. The
electron energy was set to 70 eV and the ion source temperature to
200 °C. The oven program temperature was 80 °C (2 min)//10 °C/
min//280 °C (3 min). Hydroxymethylated keto esters 7,[10] 9,[14]
11,[15] 13[16] and 15[8] are known to literature and 1H and 13C-NMR
spectra of all products correspond to data reported in the literature.
ation–lactonization.
General Procedure for the Iron-Catalyzed Hydroxymethylation of
β-Keto Esters: 2-Acetylbutyrolactone 18 (790.8 mg, 5 mmol) and
bmim-FeCl4 1 (16.8 mg, 0.05 mmol) were mixed and a 37% aque-
ous formaldehyde solution (0.45 mL, 6 mmol) was added to the
violet solution. The reaction was stirred at room temp. until TLC
indicated complete conversion. Water was evaporated under re-
duced pressure and the remaining yellow slurry was directly sub-
jected to flash column chromatography (30 g silica, light petroleum
ether/ethyl acetate, 4:1) to yield the hydroxymethylated lactone 19
as colourless liquid (537.7 mg, 68%).
3-Acetyl-4,5-dihydro-3-(hydroxymethyl)furan-2(3H)-one (19): 1H
NMR (200 MHz, CDCl3): δ = 4.37 (m, 1 H), 4.25 (dd, J1 = 16.14,
J2 = 8.51 Hz, 1 H), 4.04/3.97 (2 d, J = 11.15 Hz, 2 H), 2.73 (2dd,
J1 = 7.48, J2 = 4.16 Hz, 2 H), 2.38 (m, 1 H), 2.33 (s, 3 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 202.4, 175.2, 66.7, 64.3, 63.1,
27.9, 26.5 ppm. C7H10O4·0.2H2O (174.15): calcd. C 51.98, H, 6.48;
found C 52.00, H, 6.73.
[a] Reactions were performed with 5 mmol keto ester 6, 6 mmol aq.
HCHO and 0.5 mmol bmim-FeCl4 (1) at 80 °C overnight. [b] Iso-
lated yield after flash column chromatography.
General Procedure for the Iron-Catalyzed Hydroxymethylation of
Diethyl Acylsuccinates: Diethyl acetylsuccinate (20) (1.080 g,
5 mmol) and bmim-FeCl4 (1) (168.1 mg, 0.5 mmol) were mixed and
a 37% aqueous formaldehyde solution (0.45 mL, 6 mmol) was
added. The reaction was stirred at 80 °C for 2 h until TLC indicated
complete conversion. Water was evaporated under reduced pressure
and the remaining slurry was directly subjected to flash column
chromatography (30 g silica, light petroleum ether/ethyl acetate,
3:1) to yield the tetrahydrofuran-3-carboxylate 21 as colourless oil
Conclusions
In summary, we have established a successful approach
to iron-catalyzed hydroxymethylation of various β-keto
esters using the iron-containing ionic liquid bmim-FeCl4 1. (850.8 mg, 85%).
The reaction could be directly performed in aqueous form-
aldehyde solution without further addition of co-solvents
and surfactants. Besides, the amount of iron catalyst was
Ethyl 3-Acetyl-2,3,4,5-tetrahydro-5-oxofuran-3-carboxylate (21): 1H
NMR (200 MHz, CDCl3): δ = 4.56 (s, 2 H), 4.23 (q, J = 7.11 Hz,
2 H), 3.04/2.93 (2 d, J = 18.0 Hz, 2 H), 2.20 (s, 3 H), 1.25 (t, J =
considerably reduced compared to literature values and a 7.14 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 198.8, 173.1,
Eur. J. Org. Chem. 2008, 3453–3456
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3455

K. Bica, P. Gaertner
SHORT COMMUNICATION
168.8, 69.7, 62.9, 62.3, 33.5, 26.0, 13.7 ppm. GC-MS (EI+): Rt =
14.05 min; m/z (%) = 201.1 (1) [M+ + 1], 158.1 (60), 140.0 (100),
129.0 (16), 124.0 (17), 113.1(40), 112 (56), 98.9 (24), 86.1 (33), 67.9
(27). C9H12O5 (200.19): calcd. C 54.00, H 6.04; found C 53.82, H
5.90.
Acknowledgments
Financial support given by the Hochschuljubiläumsstiftung der
Stadt Wien is gratefully acknowledged.
[1] a) P. Dyson, S. Tavener, D. Adams, Chemistry in Alternative
Reaction Media, Wiley, Chichester, 2003; b) R. A. Sheldon,
Green Chem. 2005, 7, 267–278.
[2] a) P. Wasserscheid, T. Welton (Eds.), Ionic Liquids in Synthesis,
2nd ed., Wiley-VCH, Weinheim, 2008; b) V. I. Parvulescu, C.
Hardacre, Chem. Rev. 2007, 107, 2615–2665.
[3] For a recent example: D. Yin, C. Li, L. N. Yu, S. Hu, D. Yin,
J. Mol. Catal. A 2006, 245, 260–265.
[4] C. Bolm, J. Legros, J. Le Paih, L. Zani, Chem. Rev. 2004, 104,
6217–6254.
Ethyl 2,3,4,5-Tetrahydro-5-oxo-3-propionylfuran-3-carboxylate (23):
1H NMR (200 MHz, CDCl3): δ = 4.59 (s, 2 H), 4.25 (q, J =
7.11 Hz, 2 H), 3.06/2.95 (2 d, J = 18.2/18.0 Hz, 2 H), 2.49 (q, J =
7.17 Hz, 2 H), 1.26 (t, J = 7.14 Hz, 3 H), 1.07 (t, J = 7.14 Hz, 3
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 202.0, 173.2, 169.1, 70.1,
62.9, 62.1, 33.9, 32.2, 13.8, 7.8 ppm. GC-MS (EI+): Rt = 12.56 min;
m/z (%) = 215.2 (0.4) [M+ + 1], 185.2 (1), 157.2 (3), 140.1 (5),
127.1 (3), 113.2 (3), 101.1 (3), 85.1 (4), 83.2 (4), 68.1 (2), 57.1 (100).
C10H14O5 (214.22): calcd. C 56.07, H 6.59; found C 56.15, H 6.57.
[5] K. Bica, P. Gaertner, Org. Lett. 2006, 8, 733–735.
[6] For reviews: a) B. B. Snider in Comprehensive Organic Synthesis
(Eds: B. M. Trost, I. Fleming), Pergamon Press, Oxford, 1991,
vol. 2, pp. 527–561; b) R. Mahrwald, Modern Aldol Reaction,
Wiley-VCH, Weinheim, 2004, vol. 2; c) C. Palomo, M. Oiar-
bide, J. M. Garc´ia, Chem. Soc. Rev. 2004, 33, 65–75.
[7] a) A. Guzaev, H. Lönnberg, Synthesis 1997, 11, 1281–1284; b)
H. Torii, M. Nakadai, K. Ishihara, S. Saito, H. Yamamoto,
Angew. Chem. Int. Ed. 2004, 43, 1983–1986; c) P. Poijärvi, E.
Mäki, J. Tomperi, M. Ora, M. Oivanen, H. Lönnberg, Helv.
Chim. Acta 2002, 85, 1869–1876; d) J. Casas, H. Sundén, A.
Córdova, Tetrahedron Lett. 2004, 45, 6117–6119; e) I. Fukuchi,
Y. Hamashima, M. Sodeoka, Adv. Synth. Catal. 2007, 349,
509–512.
[8] V. Lecomte, C. Bolm, Adv. Synth. Catal. 2005, 347, 1666–1672.
[9] C. Ogawa, S. Kobayashi, Chem. Lett. 2007, 36, 56–57.
[10] a) H. Kuwano, K. Haraguchi, H. Tanaka, T. Nitanda, M.
Baba, G. E. Dutschman, Y.-C. Cheng, K. Kato, Nucleosides
Nucleotides Nucleic Acids 2005, 24, 73–83; b) Y. Cheng, H.
Tanaka, M. Baba, US Pat. 167096, 2004.
[11] J. Dupont, C. S. Consorti, P. A. Z. Suarez, R. F. de Souza, Org.
Synth. 2003, 79, 236–243.
[12] a) S. Hayashi, H. Hamaguchi, Chem. Lett. 2004, 33, 1590–
1591; b) M. S. Sitze, E. R. Schreiter, E. V. Patterson, R. G.
Freeman, Inorg. Chem. 2001, 40, 2298–2304; c) Q. Zhang, J.
Yang, X. Lu, J. Gui, M. Huang, Fluid Phase Equilib. 2004, 226,
207–211.
[13] a) T. M. Patrick, J. Org. Chem. 1952, 17, 1009–1016; b) B.
Metten, M. Kostermans, G. Van Baelen, M. Smet, W. Dehaen,
Tetrahedron 2006, 54, 6018–6028; c) P. A. Wehrle, V. Chu, Org.
Synth. 1978, 58, 79–82.
[14] T. H. Chan, A. E. Schwerdtfeger, J. Org. Chem. 1991, 56, 3294–
3298.
Ethyl 3-Butyryl-2,3,4,5-tetrahydro-5-oxofuran-3-carboxylate (25):
1H NMR (200 MHz, CDCl3): δ = 4.55 (s, 2 H), 4.20 (q, J =
7.17 Hz, 2 H), 3.01/2.91 (2 d, J = 18.0 Hz, 2 H), 2.40 (q, J =
6.94 Hz, 2 H), 1.56 (t, J = 7.36 Hz, 2 H), 1.22 (t, J = 7.12 Hz, 3
H), 1.07 (t, J = 7.14 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 201.1, 173.1, 168.9, 69.1, 62.8, 62.1, 40.4, 33.6, 16.8, 16.7,
13.2 ppm. GC-MS (EI+): Rt = 13.34 min; m/z (%) = 229.2 (0.4)
[M+ + 1], 185.1 (1), 157.1 (3), 127.0 (2), 101.1 (2), 85.1 (3), 71.2
(100), 55.1 (3). C11H16O5 (228.24): calcd. C 57.88, H 7.07; found C
58.00, H 7.01.
Ethyl
2,3,4,5-Tetrahydro-3-isobutyryl-5-oxofuran-3-carboxylate
1
(27): H NMR (200 MHz, CDCl3): δ = 4.55 (s, 2 H), 4.20 (q, J =
7.11 Hz, 2 H), 3.03/2.93 (2 d, J = 18.0 Hz, 2 H), 2.78 (sept, J =
6.71 Hz, 1 H), 1.22 (t, J = 7.14 Hz, 3 H), 1.03 (d, J = 6.65 Hz, 6
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 205.8, 173.2, 169.0, 70.0,
62.9, 62.4, 37.7, 33.8, 19.7, 19.6, 13.8 ppm. GC-MS (EI+): Rt =
12.84 min; m/z (%) = 229.2 (1) [M+ + 1], 185.1 (2), 157.0 (4), 140.0
(3), 127.1 (6), 113.1 (9), 99.0 (5), 86.1 (8), 71.1 (100), 68.1 (4).
C11H16O5 (228.24): calcd. C 57.88, H 7.07; found C 58.06, H 7.14.
Ethyl 3-Benzoyl-2,3,4,5-tetrahydro-5-oxofuran-3-carboxylate (29):
1H NMR (200 MHz, CDCl3): δ = 7.75 (m, 2 H), 7.59 (m, 1 H), 7.45
(m, 2 H), 4.88/4.75 (2 d, J = 9.78 Hz, 2 H), 4.15 (q, J = 7.11 Hz, 2
H), 3.26 (s, 2 H), 1.02 (t, J = 7.14 Hz, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 191.0, 173.1, 170.1, 134.1, 133.3, 129.0,
128.6, 70.7, 62.9, 59.7, 35.1, 13.5 ppm. GC-MS (EI+): Rt
=
17.40 min; m/z (%) = 262.2 (0.1) [M+], 157.1 (2), 106.2 (7), 105.1
(100), 78.2 (2), 77.1 (24), 51.1 (3). C14H14O5 (262.26): calcd. C
64.12, H 5.38; found C 64.27, H 5.17.
[15] T. Akeboshi, Y. Ohtsuka, T. Sugai, H. Ohta, Tetrahedron 1998,
54, 7387–7394.
[16] R. Longeray, J. Dreux, Bull. Soc. Chim. Fr. 1964, 11, 2849–
2853.
Supporting Information (see also the footnote on the first page of
1
this article): Copies of H and 13C spectra of all new and known
Received: March 27, 2008
compounds.
Published Online: May 30, 2008
3456
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3453–3456